Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma

This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9–39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0–20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16–53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3–35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

I) Abnormal p53 staining (null pattern) in endometrial carcinoma; no staining is seen in is seen in tumor cell nuclei. Note the presence of faint wild-type staining in background non-tumor nuclei, serving as an internal positive control. J) Positive PD-L1 staining in endometrial carcinoma, predominantly seen in intratumoral immune cells, with lesser expression in viable tumor cells K) PD-L1-negative endometrial carcinoma L) Endometrial carcinoma with retained PTEN staining M) Loss of PTEN expression in endometrial carcinoma; note retained staining in peritumoral stroma, serving as a positive internal control  Primary Objectives • To determine the antitumor activity of single agent niraparib and of niraparib in combination with TSR-042 in women with metastatic endometrial cancer who previously received platinum-based chemotherapy, via assessment of clinical benefit rate (complete response, partial response or stable disease ≥16 weeks) according to RECIST v 1.1.

Secondary Objectives
• To assess the safety and tolerability of single agent niraparib and the combination of niraparib and TSR-042 • To determine overall response rate, duration of response, progression free survival and overall survival of niraparib and the combination of niraparib and TSR-042 Exploratory/Translational Objectives • To assess if phosphatase and tensin homolog (PTEN) loss as assessed by immunohistochemistry (IHC) in archival tumor is predictive of response to treatment • To assess if microsatellite instability (MSI) in archival tumor is predictive of response to treatment • To assess the correlation of homologous recombination defect (HRD) status and response to treatment • To correlate HRD with PTEN and MSI status respectively • To assess genomic molecular analysis and response to treatment • To assess the immune infiltration by PD-L1, CD3, CD8, CD20, CD21.

Study Design:
The purpose of this trial is to elucidate whether the PARP inhibition approach with niraparib, or the combination of niraparib and TSR-042, provides clinical benefit in patients with recurrent endometrial cancer. The trial is designed as a multicenter, open-label, phase II study of niraparib in monotherapy or in combination with anti-PD1 inhibitor TSR-042 in recurrent endometrial cancer. Patients must have received prior platinum based chemotherapy.
The study will initially enroll patients with recurrent endometrial cancer to the niraparib monotherapy cohort not selected according to the PTEN status (cohort I).
Once the initial assessment with niraparib monotherapy is completed (inclusion of 22 evaluable patients), patients will be enrolled in the combination arm with niraparib and TSR-042 (cohort II). If patients do not meet the pre-specified criteria for clinical efficacy, retrospective analysis of PTEN status in cohort I will be performed while we enroll patients in cohort II and consider further enrichment of PTEN loss. Results will be available prior to end of cohort II. If the archival tissue was inadequate for PTEN analysis, patient might be replaced for the total number of patients required in cohort I. The study may continue on the selected population of patients with PTEN-loss on IHC (archival tissue or tumor biopsy).

Number of patients:
The minimal accrual in cohort I, stage I and II is 22 patients; 10 patients for stage I and 12 patients for stage II. After 22 patients are enrolled in cohort I, additional 22 patients will be enrolled in cohort II, assessing the combination of niraparib and TSR-042.
The cohort may be considered for expansion up to 44 patients after completion of enrollment of initial 22 patients in cohort I.

Main criteria for Inclusion/Exclusion (refer section 3.1 & 3.2 for details)
Inclusion Criteria 1. Histologically confirmed epithelial endometrial cancer. All histological subtypes are allowed except for endometrial sarcoma, carcinosarcoma, clear cell, mixed and adenosquamous tumors. 2. Patients must have radiographic evidence of disease progression following the most recent line of treatment. 3. Patients must have previously received at least one line of platinum-based chemotherapy. Prior hormonal and immunotherapy are allowed. There is no restriction on the total number prior lines of therapy. 4. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as ≥10 mm with CT scan, MRI, or calipers by clinical exam, and ≥15mm for nodal lesions. Areas of previous radiation may not serve as measurable disease unless there is evidence of progression post radiation. 5. Patients must have archival tumor sample available for PTEN analysis. If archival tissue is not available, the patient will have the option to undergo tumor biopsy. 6. Eastern Cooperative Group (ECOG) performance status ≤ 2. 7. Life expectancy of greater than 12 weeks. 8. Within 7 days of the proposed start of treatment, patients must have normal organ and marrow function as defined below: Hemoglobin ≥ 90 g/L Leukocytes (WBC) ≥ 3.0x10 9 /L Absolute neutrophil count ≥ 1.5x10 9 /L Platelets ≥ 100x10 9 /L Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 3.0 × institutional upper limit of normal unless liver metastases are present, in which case they must be ≤ 5 x ULN Creatinine ≤ 1.5 × institutional upper limit of normal OR Calculated creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation Serum albumin ≥ 28g/L 9. Women must agree to not donate blood during the study or for 90 days after the last dose of study treatment, in cohort II. Additional inclusion for Cohort II only: 10. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN 11. Participant receiving corticosteroids may continue as long as their dose is stable for at least 4 weeks prior to initiating protocol therapy 12. Participant must agree not to breastfeed during the study or for 150 days after the last dose of study treatment.
Exclusion Criteria 1. Chemotherapy or biologic agents received within 4 weeks of starting study treatment. 2. Hormonal therapy within 2 weeks of starting study treatment. 3. Pelvic radiotherapy (as treatment of primary disease) within 4 weeks, or palliative radiotherapy encompassing >20% of the bone marrow within 1 week of starting study treatment. 4. Previous treatment with a PARP inhibitor, or any other targeted therapy directed against the homologous recombination pathway. 5. Patients who are receiving any other investigational agents. 6. Ongoing ≥ Grade 2 toxicities related to prior cancer therapy, with the exceptions of alopecia, neuropathy, lymphopenia and skin depigmentation. 7. Received transfusion (platelets or red blood cells) ≤4 weeks of the first dose of study treatment. 8. Major surgery within 4 weeks of registration or ongoing clinically significant postsurgical complications. Study biopsy is not considered major surgery. 9. Known brain metastases, except if stable for greater than 28 days following definitive treatment. The patient must have no new or progressive signs or symptoms related to the CNS disease and must be either off or taking a stable dose of corticosteroids. A scan to confirm the absence of brain metastases is not required. 10. History of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). 11. History of bowel obstruction within 3 months, or other reason preventing effective oral administration of medication. 12. Known history of human immunodeficiency virus (type 1 or 2 antibodies). 13. Uncontrolled inter-current illness. 14. History of other malignancy ≤ 3 years prior to registration with the exceptions of a) cone-biopsied in situ carcinoma of the cervix uteri; b) basal or squamous cell carcinoma of the skin. All second malignancies in this context should be discussed with the PI.
Additional exclusion for Cohort II only: 15. Previous treatment with anti PD-1, anti PD-L1, antiPDL2, anti CTLA4 agents History of fistula, or high-risk of developing a fistula. 16 In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies: • Any treatment-related Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 events that have not reverted to baseline or CTCAE Grade 1 or better within 28 days. At the Investigator's discretion, following dose interruption (no longer than 28 days), patients may be considered for dose reductions provided they have not already undergone the maximum allowed number of 2 dose reductions. If upon re-challenging with study treatment at the lowest allowable dose, any CTCAE Grade 3 or 4 adverse events recur, the patient should stop treatment • If platelet count has not reverted to ≥100x10 9 /L within 28 days of treatment interruption. • Delays in TSR-042 treatment will be allowed for 4 weeks, if there is benefit in restarting the treatment, it will be discussed with the PI. TSR-042 can be continued for a maximum of 2 years.
• Patient decides to withdraw from the study, or • General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.

Correlatives:
• To assess whether the presence PTEN deficiency in archival tumor is predictive of clinical benefit and response to treatment • To explore whether the presence of MSI status is predictive of clinical benefit and response rate to treatment • To correlate HRD with PTEN and MSI status respectively. • To explore whether HRD positivity in endometrial cancer is predictive of clinical benefit and response rate to treatment • To assess the immune infiltration by PD-L1, CD3, CD8, CD20, CD21

Statistics:
The Simon two-stage design is employed. With the null hypothesis that Clinical benefit rate (CBR), p ≤ 0.10 versus the alternative that p ≥ 0.35 and setting alpha=beta=0.10, Stage I has a planned accrual of 10 patients. If at least 1 clinical benefit instance is observed at the end of stage I, the study will proceed to stage II with 12 additional patients to be accrued for the total of 22 patients. If at least 5 instance of clinical benefit are observed among the 22 patients, this agent would be considered worthy of further investigation. The study will enroll patients with recurrent endometrial cancer unselected for PTEN status. Mandatory archival tissue is requested for retrospective analysis.
After the enrollment of a total of 22 patients in cohort I (niraparib alone), new patients will be registered in cohort II with the combination of niraparib and TSR-042. If at least 5 instance of clinical benefit are observed among the 22 patients in cohort II, this agent would be considered worthy of further investigation.
If the clinical benefit rate does not reach the pre-defined level (positive ≥5/22 overall) after stage II in cohort I, PTEN analysis will be performed and the study will be considered to expand to PTEN-loss subgroup if this subgroup's CBR is not worse than the rest of the patients initially in cohort 1 with niraparib single agent. The same criteria as calculated by the design above (≥1/10 CBR go to stage II and positive ≥5/22 CBR overall) will be used.

OBJECTIVES
Targeting the homologous recombination (HRD) pathway has emerged as an attractive therapeutic strategy in endometrial cancer. Thus, the purpose of this trial is to elucidate whether the PARP inhibition approach with niraparib, or the combination of niraparib and TSR-042, provides clinical benefit in patients with recurrent endometrial cancer. This study will recruit patients with recurrent endometrial cancer previously treated with platinum based chemotherapy.

Primary Objectives
• To determine the antitumor activity of single agent niraparib and of niraparib in combination with TSR-042 in women with metastatic endometrial cancer who has received prior platinum-based chemotherapy via assessment of clinical benefit rate (complete response, partial response or stable disease ≥16 weeks), according to RECIST v 1.1.

Secondary Objectives
• To assess the safety and tolerability of single agent niraparib and of niraparib in combination with TSR-042. • To determine overall response rate, duration of response, progression free survival and overall survival of niraparib and the combination of niraparib and TSR-042

Exploratory Objectives
• To assess if PTEN loss as assessed by immunohistochemistry (IHC) in archival tumor is predictive of response to treatment • To assess if MSI in archival tumor is predictive of response to treatment • To assess the correlation of HRD status and response to treatment • To correlate HRD with PTEN and MSI status respectively • To assess genomic molecular analysis and response to treatment • To assess the immune infiltration by PD-L1, CD3, CD8, CD20, CD21.

Disease Background
Endometrial cancer is the highest incidence gynecologic malignancy and remains the fourth most common cancer diagnosis in North American women [1]. In 2012, there were approximately 5,600 new cases of endometrial cancer in Canada, from whom it is estimated that 900 women will die of their disease [2].
The main risk factor for the development of endometrial cancer continues to be prolonged exposure to unopposed estrogen [3]. Other identified risk factors (nulliparity, use of tamoxifen, hormone replacement therapy etc) are likely relevant due to the pathology-promoting imbalance of estrogen/progesterone [4]. The ever growing obesity epidemic with its consequent metabolic syndromes is yet another factor promoting estrogenic imbalances in women and is likely a major contributing factor to the burden of disease we currently see related to endometrial cancer [5].
Endometrial cancer is predominantly a disease of older women who present with aberrant postmenopausal bleeding as the first symptom of their disease [6]. The majority of women are diagnosed with early stage disease and have a relatively good prognosis, with 5-year disease-free survivals of greater than 80% [7]. Surgery continues to be the mainstay of management; however, chemotherapy and radiation have demonstrated utility at reducing the risk of local and distant disease recurrence and have now become standard practice [8]. However, a significant percentage of women with early stage disease are at a greater risk of developing disease recurrence. Factors like age > 60, depth of invasion, involvement of lower uterine segment, non-endometroid histology and the presence of lymphovascular invasion or aneuploidy, have demonstrated importance in identifying those at a particularly high risk of failing primary therapy [8]. Women with more advanced disease at initial presentation have a relatively poor prognosis with a 5-year disease free survival of about 20% [7].
There is significant heterogeneity within this group, as patients with endometroid histology tend to respond to hormonal manipulation while patients with high grade serous cancers follow a more aggressive course and benefit from a limited number of cytotoxic therapies. The best responses are to agents like doxorubicin and cisplatin, although these responses remain modest and in the range of ~ 20 to 40% and where noted are transient in duration [9,10]. Although combination regimens have demonstrated higher response rates, the associated increased toxicities and unclear impact on survival makes their role in the palliative setting uncertain.

Relevance of Histopathology and Molecular Characterization
In the past 30 years, endometrial cancer has been broadly classified into two subtypes on the basis of histological characteristics, hormone receptor expression, and grade [11]. The majority of patients are diagnosed with endometroid adenocarcinomas known as Type I cancers, which are characteristically low-grade, on a background of atypical complex hyperplasia [11]. They express hormone-receptors and are usually associated with a good prognosis. Type II endometrial cancers are described as non-endometrioid, high grade, aneuploid, TP53-mutated, hormone-receptor negative tumors that are associated with a higher risk of metastasis and a poor prognosis [11]. This group also includes clear cell, carcinosarcoma and stromal sarcomas albeit at much lower frequencies all with their own unique clinical and molecular profiles [11]. Comprising a small proportion of all uterine cancers, non-endometroid histology cancers account for about 50% cases of recurrent disease and therefore represent a significant management challenge [6]. Whilst this dualistic classification has begun being incorporated into clinical decision-making algorithms defining high-risk patients, its prognostic value remains limited given 20% of endometrioid (i.e. type I) endometrial cancers relapse; whereas 50% of non-endometrioid (i.e., type II) endometrial cancers do not [6]. Additionally, 15-20% of endometrioid tumors are high-grade lesions, and where they fit into the dualistic model is unclear [12,13].
Endometrial cancer comprises a range of diseases with distinct genetic and molecular features. Analyses by The Cancer Genome Atlas (TCGA) focusing on endometrioid and serous endometrial cancer further emphasize the disease's heterogeneity [14]. Within type I endometrial cancer, the PIK3/AKT/mTOR pathway is the commonest genetic aberration, with mutations noted in more than 90% of tumors. Furthermore, molecular alterations in the negative regulator of this pathway, PTEN, are common-including PTEN mutations (77%) or loss of PTEN heterozygosity (40%). PIK3CA mutations (42-53%). KRAS mutations (25% of tumors), CTNNB1 (37%), ARID5B (35%), and FGFR2 mutations (12%) are also frequently seen [14,15].  [14,16]. Clear-cell endometrial cancer resembles its ovarian clear-cell counterpart, with inactivating mutations in the chromatin remodeling gene ARID1A in 20-40% of cases and universal expression of hepatocyte nuclear factor-1β [17][18][19]. Interestingly, a substantial overlap in genetic defects occurs within endometrial cancer subtypes. PIK3CA mutations, commonly presented in type I tumors, are also present in up 40% serous endometrial cancer, and the presence of concomitant molecular deficiencies have also been described, showing the heterogeneity of this disease [14].
TCGA investigations identified four distinct molecular subgroups: POLE ultramutated, microsatellite instability (MSI) hyper mutated, copy-number-low microsatellite stable, and copynumber-high serous-like, showing increasing grade, TP53, and high somatic copy number alterations, but decreased mutation rates [14]. The newly identified POLE ultramutated category is the smallest subgroup, but defines a unique subset characterized by mutations in the exonuclease domain of POLE, high mutation load, and an excellent prognosis [20]. Approximately 60% of POLE ultramutated endometrial cancers are high-grade endometrioid lesions, and 35% harbor TP53 mutations. Roughly 30-40% of endometrioid endometrial cancers show loss of DNA mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2); in sporadic cases this is secondary to MLH1 promoter hypermethylation, and in hereditary Lynch syndrome it can be caused by mutations in any of the DNA MMR genes [21,22]. The microsatellite stable subgroup is characterized by low mutation load, a low rate of somatic copy number alterations, and intermediate prognosis [14]. The copy-number high subgroup includes most serous endometrial cancers and 25% of the high-grade endometrioid cancers that display genomic instability, with frequent somatic copy number alterations and poor prognosis [14]. High-grade endometrioid endometrial cancers are heterogeneous-25% are copy-number-high serous endometrial cancers with poor prognosis; another quarter are ultramutated POLE cancers, which have good prognosis [14]. Given the inherent heterogeneity in this patient population with respect to both clinical course and therapeutic response, there is optimism that novel approaches aimed specifically at differential vulnerabilities within different molecular subgroups of this disease will improve outcomes for patients with endometrial cancer.

BACKGROUND Immune Surveillance and PD-1 Inhibitors
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and prognosis in various malignancies. [23][24][25][26][27][28][29][30][31][32][33][34][35] In particular, the presence of cluster of differentiation (CD)8+ T cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells seem to correlate with improved prognosis and long-term survival in many solid tumors. [31,[36][37][38][39][40][41][42] The programmed death-1 (PD-1) receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. [43] The normal function of PD-1, expressed on the cell surface of activated T cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (programmed death-ligand 1 [PD-L1] and programmed death-ligand 2 [PD-L2]). The structures of murine PD-1 alone [44] and in complex with its ligands were the first to be resolved, [45,46] and more recently the nuclear magnetic resonance-based structure of the human PD-1 extracellular region and analyses of its interactions with its ligands were also reported. [47] PD-1 and family members are Type I transmembrane glycoproteins containing an Ig variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail, which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM within its cytoplasmic tail, leading to the dephosphorylation of effector molecules, such as CD3ζ, PKCθ, and ZAP70, which are involved in the CD3 T cell signaling cascade. [48] The mechanism by which PD-1 down-modulates T cell responses is similar to, but distinct from, that of CTLA-4. [49] PD-1 was shown to be expressed on activated lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, T regs, and natural killer cells. [50] Expression has also been shown during thymic development on CD4-/CD8-(double-negative) T cells, [51] as well as subsets of macrophages [52] and dendritic cells. [53] The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types. [54] PD-L1 is expressed at low levels on various nonhematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is predominantly expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. [54] Both ligands are Type I transmembrane receptors containing both IgV-and IgC-like domains in the extracellular region and short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T cell activation triggered through the T cell receptor. PD-L2 is thought to control immune T cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T cell function in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T cell inhibitor, [55,56] which, via its interaction with the PD-1 receptor on tumor-specific T cells, plays a critical role in immune evasion by tumors. [57] As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in cancer. [58] Immune surveillance in endometrial cancer Two subgroups of endometrial cancer, POLE-ultra-mutated and MSI-H, are characterized by higher number of neo-antigens and the elevated amount of TILs [59].
In 2015 Le et al. published a phase II trial leading to the approval of Pembrolizumab, an antiprogrammed death 1 (anti-PD1) immune checkpoint inhibitor, in MSI solid tumours. Study population was divided in three cohorts, including patients with MMR-deficient colorectal cancer, MMR proficient colorectal cancer and MMR-deficient solid tumours (non-colorectal). The third cohort included two patients with endometrial carcinoma, showing immune-related objective response rate (ORR) and PFS of 71% and 67%, respectively. Moreover, there was a higher immune-related ORR and 20-week immune related progression free survival (PFS), 40% and 78%, respectively, in the MMR deficiency cohorts, versus 0% and 11% in MMR proficient colorectal patients [60]. On an update of the study, ORR was observed in 53% of patients and complete responses were achieved in 21% of patients [61]. Long responses have also been described in case series of patients with POLE mutated and MSI endometrial tumours with other anti-PD1 treatments [62].
Similarly, other early studies have been done including women with endometrial cancer without MSI or POLE molecular screening. On KEYNOTE-028 is a phase Ib study in patients with programmed death ligand 1 (PD-L1) -positive advanced solid tumors progressing to standard treatment, of whom 24 had endometrial tumours and 2 where SC. ORR was 13%, three patients obtained a partial response and other three stable disease. Six-months PFS and OS rates were 19.0% and 68.8% respectively [63].
Combination trials with anti-PD1/PDL1 have also been published. A phase I / II trial with 23 women treated with Lenvatinib and Pembrolizumab showed an ORR of 48% and a diseasecontrol rate of 96%. The most common adverse events were hypertension, fatigue, arthralgia, diarrhea and nausea [64].

Background of PARP and PARP Inhibition
Poly(ADP-ribose) polymerases (PARP-1 and -2) are zinc-finger deoxyribonucleic acid (DNA)binding enzymes that play a crucial role in DNA repair [65]. Upon formation of single-strand DNA breaks, PARP binds at the end of broken DNA strands, thus activating its enzymatic activity. Activated PARP catalyzes the addition of long polymers of ADP-ribose on several proteins associated with chromatin, including histones and various DNA repair proteins including PARP itself [66][67][68]. This results in chromatin relaxation, fast recruitment of DNA repair proteins and efficient repair of DNA breaks. In this manner, PARP plays a central role in sensing DNA damage and converting it into intracellular signals that activate the base-excision-repair (BER) and single strand break repair pathways [66][67][68].
Normal cells repair up to 10,000 DNA defects daily and single strand breaks are the most common form of DNA damage. Cells unable to repair this burden of DNA damage-such as those with defects in the BER pathway, or those treated with PARP inhibitors-are at risk for accumulating multiple lesions that will ultimately trigger apoptosis as they progress to enter the S (DNA replication) phase of the cell cycle with unrepaired single strand breaks [69]. Pre-existing single strand breaks are converted to double strand breaks as the replication machinery passes and those accumulated double strand breaks present during S phase are then repaired by homologous recombination [69]. Homologous recombination is the preferred repair pathway because it is associated with a much lower error rate than other forms of repair. Cells unable to perform DNA repair via homologous recombination (e.g., due to inactivation of genes required for homologous recombination, such as BRCA-1 or BRCA-2) are at risk for accumulating multiple lesions that will ultimately trigger apoptosis [69]. Specifically, these cells accumulate stalled replication forks during S phase and are more likely to use the error-prone non-homologous end joining (NHEJ) pathway to repair double strand breaks in DNA [70]. It is the accumulation of errors in DNA by NHEJ that contributes to mutations promoting the development of cancer. Over time, the buildup of excessive DNA errors in combination with the inability to complete S phase (because of stalled replication forks) contributes to cell death [70].
A hypothesis is that treatment with PARP inhibitors represents a novel opportunity to selectively kill a subset of cancer cells with deficiencies in DNA repair pathways. For example, a tumor arising in a patient with a BRCA1/2 mutation (BRCAmut) has a defective homologous recombination DNA repair pathway and would be increasingly dependent on BER (a pathway blocked by PARP inhibitors) for maintenance of genomic integrity [69]. Non-BRCA deficiencies in homologous recombination DNA repair genes could also enhance tumor cell sensitivity to PARP inhibitors. The rationale for anticancer activity in a subset of non-BRCAmut tumors is they share distinctive DNA-repair defects with gBRCAmut carriers, a phenomenon broadly described as "BRCAness" [71]. DNA-repair defects can be caused by germline or somatic alterations to the homologous recombination DNA repair pathway. In an analysis of ~500 high grade serous ovarian cancer, approximately 50% contained HR defects [72]. These tumors had biologically plausible molecular alterations that may make them sensitive to PARP inhibition, such as with niraparib. This concept of inducing death by use of PARP inhibitors to block one DNA repair pathway in tumors with preexisting deficiencies in a complementary DNA repair pathways is called synthetic lethality [73], the two insults together induce cell death when neither alone would have this effect.
Clinical studies have shown that PARP inhibitors are active for recurrent ovarian cancer [74][75][76][77]. Clinical anticancer activity has been observed in patients with and without gBRCAmut and in patients who are platinum sensitive and platinum-resistant; however, PARP inhibition appears to be most active in patients with BRCA mutated disease [74,75,77,78]. This clinical experience to date is largely in patients who have received multiple prior treatments (median 3, range 1-10) in multiple early phase clinical studies. In a phase 2 study of maintenance therapy in 265 patients with relapsed, platinum-sensitive ovarian cancer, daily olaparib therapy compared to placebo treatment was associated with a progression free survival (PFS) benefit (hazard ratio [HR]: 0.35) and prolongation of median PFS from 4.8 months to 8.4 months [77]. The subset of patients with known BRCAmut had a PFS hazard ratio of 0.1. Patient reported outcomes (PROs) in this study, which included the Functional Assessment of Cancer Therapy -Ovarian Symptoms Index (FOSI), were measured and were not found to show a significant difference between the placebo and treatment groups; thus, suggesting maintenance treatment did not decrease functioning or quality of life in these patients [77].

Characterization of Niraparib
The chemical name for niraparib is ( . The current clinical formulation of niraparib is a dry-filled capsule available in 100 mg. Niraparib is an orally selective PARP1/2 inhibitor that selectively kills in vitro tumor cells with inactivation of BRCA1, BRCA2 or ATM genes. In the nonclinical setting, anti-tumor activity was demonstrated in studies with BRCA1-mutant and BRCA2-mutant mouse xenograft models. In BRCA1 mutant xenograft studies, niraparib dosed orally caused tumor regression, which was mirrored by >90% reduction in tumor weight compared with the control. In BRCA2-mutant xenograft studies, niraparib-dosed mice showed 55% -60% growth inhibition (by both tumor volume and weight). Nonclinical efficacy has also been demonstrated in breast and ovarian patientderived xenograft (PDX) models that show evidence of HRD.
Results from clinical testing in Phase 1 indicated that niraparib is generally safe and well tolerated in patients with advanced solid tumors. Preliminary safety data from two Phase 3 studies (including one blinded, placebo-controlled study) also suggest that treatment with niraparib is generally well tolerated. Preclinical data on niraparib in ovarian cancer are described in the Investigator's Brochure. Niraparib clinical safety data, including Phase 1 results, dose limiting toxicities and toxicity profile are provided in detail in the Investigator's Brochure.

Chemical Structure
The chemical structure of niraparib is shown in Figure 1.

Non-clinical Development
Niraparib is an orally active PARP1/2 inhibitor with nanomolar potency being developed as a monotherapy agent for tumors with defects in the homologous recombination DNA repair pathway or that are driven by PARP-mediated transcription factors. In preclinical models, niraparib has been observed to inhibit normal DNA repair mechanisms and induce synthetic lethality when administered to cells with homologous recombination defects. In a BRCA1 mutant xenograft study, niraparib dosed orally caused tumor regression which was mirrored by >90% reduction in tumor weight compared to control; in a BRCA2 mutant xenograft study, niraparib dosed mice showed 55-60% growth inhibition, both by tumor volume and weight. Preclinical data on niraparib in ovarian cancer are provided in detail in the Investigator's Brochure (IB).

Clinical Development
Overview Niraparib has been evaluated in 144 humans in Phase 1 clinical studies. Over 500 patients (427 patients of a data cutoff date of 02 February 2015) have received niraparib or placebo in the Phase 3 clinical study program. An overview of clinical studies conducted for niraparib is presented in Table 1. Detailed information for each of these studies, including pharmacokinetic data, can be found in the Investigator's Brochure. Finally, in the overall non-BRCAmut population (with both HRD-positive and HRD-negative tumors) niraparib treatment provided statistically significant PFS benefit from median 3.9 months in control to 9.3 months in niraparib group, HR 0.45 (p<0.0001). PR-30-5011-C also contains a 14-day, open-label, 2-treatment, crossover sub-study to evaluate the effect of a high fat meal on niraparib (single dose) exposure.

Safety Safety in the Phase 1 Patient Population (Overall)
Several of the Phase 1 clinical studies were terminated for reasons that did not have to do with safety. A total of 144 patients have received treatment with niraparib as monotherapy or in combination with chemotherapy in the Phase 1 study program (Protocols PN001, PN005, PN008, PN011, and PN014). Detailed information for each of these studies, including safety data, can be found in the IB.

Safety in Phase 3 Studies
Study PR-30-5011-C The main phase III study (PR-30-5011-C) has been completed but awaiting full presentation and publication of results. As report in the press release of 29 June 2016, most common (occurred in at least 10% of patients) grade 3/4 adverse events in niraparib treated patients were thrombocytopenia (28.3%), anemia (24.8%) and neutropenia (11.2%). The treatment discontinuation rate was 14.7% for niraparib treated patients and 2.2% for control. The rates of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were similar in the niraparib (1.3%) and control (1.2%) arms. There were no treatment-related deaths. CTCAE version 4.0 was used when reporting AEs.

Baseline Platelet Count and Weight as Predictors of Thrombocytopenia.
A retrospective analysis of ENGOT-OV16/NOVA and PN001 study data identified baseline body weight of <77kg (170 lbs) or baseline platelet count <150,000/µL as significant predictors for early dose modification. Lower baseline platelets (<180x10 9 /L) were associated with an increased frequency of thrombocytopenia Grade ≥1 (76%) or Grade ≥ 3 (45%) compared to patients with higher baseline platelet counts. In addition, an exploratory analysis in the ENGOT-OV16/NOVA study showed Grade ≥3 SAEs, treatment-related adverse events, and treatment-related adverse events leading to dose modification or treatment discontinuation occurred more commonly in the weight <58 kg cohort than in the ≥77 kg cohort. In the cohort of patients with a body weight <58 kg, approximately 80% of patients had a dose reduction compared to 59% of patients with a weight greater than or equal to 77 kg. Finally, a classification tree approach was used to refine the best cut-off points for predicting the likelihood of a patient developing ≥Grade 3 thrombocytopenia within 30 days after the first dose of niraparib. The results of the model show that the subgroup of patients with a baseline body weight <77 kg or baseline platelet count <150,000 µL had a grade 3/4 thrombocytopenia rate in the first 30 days of 35.4% compared to 11.5% in the group of patients with a body weight >77 kg and a platelet count >150,000 µL.

Background TSR-042
TSR-042 is an IgG4 humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. This antibody was generated based on a proprietary platform that utilizes affinity maturation to select highly-specific antibodies with desired functional characteristics. The functional antagonist activity of TSR-042 was confirmed in a mixed lymphocyte reaction assay, demonstrating enhanced interleukin-2 (IL-2) production upon addition of TSR-042. Furthermore, TSR-042 has an acceptable safety profile based on toxicology studies in cynomolgus monkeys. Additional information on the nonclinical and clinical experience with TSR-042 can be found in the TSR-042 IB.

Nonclinical Experience
TSR-042 binds with high affinity to human and cynomolgus monkey PD-1. TSR-042 blocks binding of soluble ligands to human PD-1 expressed on the surface of Chinese hamster ovary cells, with a 50% maximum inhibitory concentration (IC50) of approximately 1 nM. TSR-042 enhances T cell activation, as measured by the production of IL-2from activated CD4+ T cells, with a 50% maximum effective concentration (EC50) of approximately 1 nM. Full PD-1 receptor occupancy achieved by TSR-042 in human and cynomolgus monkey T cells from peripheral blood mononuclear cells was determined to occur at concentrations of approximately 1 μg/mL. Linear pharmacokinetic (PK) was observed for TSR-042 over the dose range tested of 10 to 100 mg/kg. Sex had no effect on exposure. The volume of distribution at steady state was low and suggested minimal tissue penetration, which is commonly observed for therapeutic monoclonal antibodies. Weekly administration resulted in approximately 2-to 3-fold increase in TSR-042 exposure.
Administration of TSR-042 by a weekly IV dose (5 total doses) to cynomolgus monkeys at doses of 0, 10, 30, or 100 mg/kg was well tolerated and did not result in any TEAEs on clinical signs, body weight, food consumption, ECG, ophthalmology, safety pharmacology parameters, clinical pathology, gross pathology, organ weight, or histopathology. The no-observed-adverse-effects level was ≥100 mg/kg in this study.

Clinical Experience
TSR-042 has been evaluated in one Phase 1 study to date. Study 4010-01-001 is an ongoing first-in-human Phase 1 study of TSR-042 to evaluate the safety and tolerability, PK, pharmacodynamics, and clinical activity of TSR-042 in patients with advanced solid tumors. The study is being conducted in 2 parts: • Part 1 (dose escalation) of the study used a modified 3 + 3 design to evaluate 3 ascending weight-based doses of TSR-042 as follows: 1, 3, and 10 mg/kg administered every 2 weeks (Q2W) via IV infusion.
• Part 2 of the study is being conducted in 2 subparts (Part 2A and Part 2B) to explore the safety and clinical activity of TSR-042 administered as a fixed dose (ie, not weight based).
− In Part 2A, following the completion of Part 1, the safety and tolerability of TSR-042 were evaluated at fixed doses of 500 mg every 3 weeks (Q3W) and 1,000 mg every 6 weeks (Q6W) using a modified 6 + 6 design with up to 24 patients (6 patients/cohort).
− In Part 2B, the clinical activity, tolerability, and safety of TSR-042 at the RP2D will be evaluated in patients with specific tumor types. Up to 5 tumor types may be investigated in 6 expansion cohorts with approximately 65 patients enrolled in each cohort.
As of 21 January 2017, safety data are available for 31 patients receiving TSR-042. In Part 1, 21 patients were treated with a weight-based dose of TSR-042 and had at least 4 weeks of safety monitoring: 6 patients received a dose of 1 mg/kg, 3 patients received a dose of 3 mg/kg, and 12 patients received a dose of 10 mg/kg, all administered Q2W. Dose escalation continued to a maximally administered dose of 10 mg/kg Q2W, and a maximum tolerated dose was not identified.
In Part 2A, 6 patients received a fixed dose of 1,000 mg Q6W and 6 patients received a fixed dose of 500 mg Q3W; these patients completed at least 6 weeks or 3 weeks of safety monitoring, respectively. No DLTs were observed, and both doses were declared to be safe. Based on the PK/pharmacodynamic profile and safety and tolerability data from the dose regimens evaluated in Part 1 and Part 2A, the recommended dose regimen to be used in Part 2B was determined to be 500 mg Q3W for 4 doses followed by 1,000 mg Q6W thereafter.

Nonclinical Experience
The efficacy and tolerability of niraparib in combination with anti-PD-1 therapy was evaluated in several nonclinical models. The combination was well tolerated in all of these studies. The combination was first tested in a homologous recombination-deficient ovarian cancer mouse model derived from BRCA null genetic background, [79] as PARP inhibition was previously shown to increase immune cell infiltration in BRCA-deficient models. [80] In a study of a ovarian carcinoma mouse model, [81] niraparib (50 mg/kg orally [PO] QD) and TSR-042 (5 mg/kg intraperitoneally [IP] twice weekly [BIW]) were administered to mice either alone or in combination for 16 days. The combination was tolerated with no treatment-related death. Almost all the tumors achieved complete regression upon treatment with niraparib, TSR-042, and the combination. Complete regression was first observed on treatment Day 16 in 2 of 6, 1 of 6, and 4 of 6 mice from the niraparib, TSR-042, and combination groups, respectively. These results suggest that the therapeutic approach of combining niraparib with TSR-042 may provide additional benefit for patients with homologous recombination-deficient tumors.
Niraparib and anti-PD-1 combination treatment has also been evaluated in several syngeneic models representing breast cancer 1 and breast cancer 2 (BRCA1/2) wild-type tumors, one of which was the breast cancer mouse model LPA1-T22. In study of a syngeneic transplant breast cancer model, niraparib (50 mg/kg PO QD) and anti-PD-1 antibody (10 mg/kg IV BIW) were administered to mice either alone or in combination for 15 days. While these tumors were moderately responsive to niraparib or anti-PD-1 antibody alone, with average tumor growth inhibition of approximately 50% for niraparib and 30% for PD-1 antibody, synergistic anti-tumor activity with near-complete tumor growth inhibition (>95%) was achieved with the combination. [82] In a similar study using the lung squamous syngeneic model KLN205, stronger tumor growth inhibition was observed for the combination (52.3%) than for niraparib alone (36.7%) or anti-PD-1 alone (30.5%). [83] Moreover, a window opportunity trial assessing PARP inhibitor Olaparib as neoadjuvant treatment in type I endometrial cancer, has shown a significant inhibition for cyclin D1 [84]. Additionally, ARD1A status was related with PARP1 and cyclin D1 expression [84]. ARID1A deficiency has been shown to promote mutagenesis, and is correlated with an increased mutational load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Interestingly, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. [85]. Together, these data support the therapeutic approach of combining niraparib with anti PD-1 agent in endometrial cancer.

Rationale
Standard treatment options for recurrent endometrial cancer are limited, and consist of chemotherapy, hormonal therapies and palliative care support. However, treatment responses are unpredictable, modest and often short-lived. In addition, no approved targeted therapies or reliable molecular biomarkers that predict the clinical benefit of targeted therapies is available for recurrent endometrial cancer; highlighting the need for new treatment options.
PTEN inactivation is the most frequent genetic aberration in endometrial cancer, predominantly in type I endometrial histology. In addition to type I endometrial cancer tumors, serous endometrial cancers (type II) appear to have a similar genetic background to serous ovarian carcinoma, including hallmarks of deficiency in DNA repair. PTEN has been implicated in the DNA damage response and homologous recombination process; and preclinical data have demonstrated increased sensitivity to PARP inhibition in PTEN-deficient endometrial cancer cell lines compared to wild-type PTEN cell lines [86,87].
Preclinical data has demonstrated that in addition to direct cytotoxic effects on cancer cells, DNA damaging agents such as PARP inhibitor may promote immunogenic cell death, alter the inflammatory tumor microenvironment and stimulate neoantigen production, thereby activating an antitumour immune response [88]. Moreover, type I endometrial cancer treated with PARP inhibitors have been linked to a cyclin D1 and ARID1 deficiency, which has shown to be a predictive of response to checkpoint inhibitor treatment in xenografts [84] 2

.6.1 Rationale for Targeting Homologous Recombination Deficiency (HRD) in Endometrial Cancer
In the past decade, advances in our understanding of the mechanisms involved in the DNA repair pathway and its regulation has led to the recognition of their importance as a potential cancer therapeutic strategy. The recent landmark genomic characterization by the TCGA has helped delineate the clearest picture of endometrial carcinogenesis. Whilst no specific conclusions were reached regarding the proportion of endometrial tumors harboring homologous recombination deficiencies, an interpretative analysis of the report suggests the role of DNA repair deficiencies in endometrial cancer [14]. Hotspot mutations in POLE, a catalytic subunit of DNA polymerase epsilon involved in nuclear DNA replication and repair, defined the POLE ultramutated subset. Furthermore, the copy-number low subgroup harbors high RAD50 expression, which is associated with the DNA repair process [14]. Furthermore, ATR mutations were found in 7% cases, and a significant proportion of ATR mutations (15%) were described in MSI positive subgroup [14].
Recently, the role of PTEN regulating the maintenance of genomic stability has been reported, suggesting that PTEN may be considered as a critical factor involved in the "BRCAness" phenotype in endometrial cancer [89]. The combination of PTEN deficient cells and PARP inhibition may have synergistic effects. PTEN encodes a phosphatase that negatively regulates the PI3K/AKT/mTOR pathway; PTEN also contributes to maintaining genomic stability by regulating the expression of RAD51 and CHK1 function, key proteins in homologous recombination DNA repair pathway [86,90]. In vitro experiments have demonstrated that PTEN-deficient endometrial cell lines fail to elicit RAD51 to DNA damage sites and may be sensitive to PARP inhibition through synthetic lethality process [86]. The role PTEN plays in determining response to PARP inhibitors has been also correlated with a nuclear activity of the protein, suggesting that the absence of nuclear PTEN expression by IHC could predict patient response [87]. However, a recent attempt failed to demonstrate correlation between PTEN deficiencies and response to PARP inhibitor (Olaparib-AZD2281) in endometrial cancer cell lines [91].
The loss of DNA MMR protein may be relevant to determine the importance of HRD in endometrial tumors. The MSI phenotype reported up to 20-30% of sporadic endometrial cancers, is a marker of an underlying defect in one of the MMR genes (principally MLH1 or MSH2) or aberrant methylation of the MLH1 promoter [92]. The TCGA report identified that MSI positive endometrioid tumors had a mutation rate approximately 10-fold greater than microsatellite-stable (MSS) endometrioid tumors. Among the most common genetic alterations related with DNA repair found due to the hypermutated genomic status of MSI positive tumors are Rad50 and MRE11 [14]. MRE11 protein forms part of the MRE11-Rad50-NBS1 complex, the primary sensor involved in DSBs repair, and recently, somatic MRE11 gene mutation have been shown to increase PARP inhibition sensitivity in endometrial cancer in vitro [93].
Understanding more about the molecular abnormalities involved in the sensitivity to PARP inhibition and defining potential predictive biomarkers is critical to rapidly advancing the field of PARP inhibition therapy in "BRCAness" tumors, such as endometrial cancer, and improves clinical outcomes of patients with recurrent endometrial cancer. Given the heightened prevalence of PTEN deficiency in endometrial cancer and the preclinical evidence, these tumors may prove to be another rational target for PARP inhibition.

PTEN Immunohistochemistry Analysis
The tumor suppressor gene PTEN negatively regulates the PI3K/mTOR pathway that is implicated in cell growth and proliferation. PTEN inactivation is the most frequent genetic aberration in endometrial cancer, predominantly in type I endometrial tumors. Several mTOR inhibitors have demonstrated activity and generally favorable toxicity profiles as single agents in endometrial cancer. However, no predictive biomarker or combinations of biomarkers for mTOR inhibitor activity have been identified [94]. In addition, PTEN has been implicated in the DNA damage response and homologous recombination process; and preclinical data have demonstrated increased sensitivity to PARP inhibition in PTEN-deficient endometrial cancer cell lines compared to wild-type PTEN cell lines [87,91].
PTEN mutation is one, though not the only, mechanism for functional PTEN loss. Given PTEN mutation is seen in up to 80% of the endometrioid subtype [95], the most common histology subtype in endometrial cancers [6], these tumors may prove to be another rational target for PARP inhibition. The overall incidence of PTEN mutation in endometrial cancers of all histological subtypes has been found to be 34-43% [96][97][98], though the incidence of PTEN protein loss on IHC is higher at 64% [96], suggesting there is a broader group of patients who may potentially benefit from a PARP inhibition treatment strategy. The current cohort-study design will enroll patients regardless the PTEN status across different endometrial cancer histologies and grades of disease, allowing a complete assessment of the activity of niraparib in endometrial cancer. Therefore, patients with relapsed endometrial cancer who have failed to platinum-based chemotherapy will be evaluated utilizing a design that allows a potential patient enrichment strategy. Loss of PTEN expression on IHC has been shown to correlate with PTEN inactivation [96]. In fact, examining for PTEN loss on IHC has been shown to be more sensitive than gene sequencing for PTEN mutation, for detecting underlying loss of functional of the protein [96]. The inactivation of PTEN protein was demonstrated through elevated phosphorylated S6 (pS6) level, which is a product of PI3K-AKT activation, a pathway that is usually suppressed by PTEN. PTEN negative tumors, as determined on IHC, had significantly higher pS6 scores than PTEN positive tumors [96]. As expected, majority of PTEN mutation positive tumors were negative on IHC (89%  [101]. This may serve as a common mechanism for sensitivity to PARP inhibition. Furthermore, PTEN mutation has been found to be more prevalent in the MSI positive than MSS endometrioid EC (PTEN mutational rate of 86% and 33% respectively) [97,98]. This study will encompass a MSI analysis to better understand the role of loss of DNA mismatch repair proteins as a predictive biomarker for antitumoral activity of niraparib.

HRD status
Presence of HRD in the tumor has been shown to predict for sensitivity to PARP inhibition in high grade serous ovarian cancer, as demonstrated through the maintenance studies involving rucaparib and niraparib in the ARIEL 2 and NOVA clinical trials respectively. It is therefore also highly of interest to assess HRD in endometrial cancer as a predictive biomarker to niraparib response. As mentioned, PTEN inactivation in endometrial cancer may contribute to the tumor's degree of underlying HRD. In the proposed study, endometrial cancers will be tested for underlying HRD. This may be performed using Myriad HRD test, a commercially developed companion diagnostic used in the NOVA phase III trial, and was able to identify a subgroup of patients with enhanced response to niraparib. Alternatively, a screening panel will be developed to include genes involved in cell regulation, DNA replication, DNA recombination and repair pathways. The analyses will be performed with next generation sequencing (NGS) for mutations in HRD genes and/or IHC for expression levels.

Genomic analysis
Next Generation Sequencing technology will be used to profile tumor DNA to correlate genomic alterations with response. We propose targeted panel whole-exonic sequencing (Advanced Molecular Diagnostics Lab -AMDL, CAP/CLIA; S. Kamel-Reid) or whole exome (or genome) sequencing (Genomics Program/Dr. Trevor Pugh), after examination of all slides available, the most suitable, representative blocks will be chosen.

Immune markers
Tumor-infiltrating lymphocytes (TILs) express PD-1 receptor (programmed cell death 1) and are activated by the ligand PD-L1 or PD-L2 expressed on tumor cells, macrophages and dendritic cells. PD-1 acts as checkpoint, downregulating immune response mediated by T-cell. Inhibition of PD-1 or PDL-1 results in the activation of an immune response against tumour cells.

Inclusion Criteria
To be considered eligible to participate in this study, patients must meet all of the following requirements: 3.1.1 Histologically confirmed epithelial endometrial cancer. All histologic subtypes are allowed except for endometrial sarcoma, carcinosarcoma, clear cell, mixed and adenosquamous tumors.
3.1.2 Patients must have radiographic evidence of disease progression following the most recent line of treatment.

Patients must have previously received at least one line of platinum-based chemotherapy.
Prior hormonal and immunotherapy are allowed. There is no restriction on the total number of lines of prior therapy.
3.1.4 Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as ≥10 mm with CT scan, MRI, or calipers by clinical exam, and ≥15mm for nodal lesions. See Section 11 for the evaluation of measurable disease. Areas of previous radiation may not serve as measurable disease unless there is evidence of progression post radiation. A biopsied lesion may be used as the target lesion if it is the only site of measurable disease.
3.1.5 Patients must have archival tumor sample available for PTEN analysis. If archival tissue is not available, the patient will have the option to undergo biopsy where feasible.
3.1.6 Age ≥18 years old on day of consent. As no dosing or adverse event data are currently available on the use of niraparib in patients <18 years of age, children are excluded from this study, but could be eligible for future pediatric trials.

Eastern Cooperative Group (ECOG) performance status ≤ 2 (see Appendix A).
3.1.8 Life expectancy of greater than 12 weeks.
3.1.11 Women must agree to not donate blood during the study or for 90 days after the last dose of study treatment 3.1.12 Women of child-producing potential must agree to use two highly effective contraceptive methods prior to study entry, during study participation, and for at least 150 days after the last administration of study medication. A serum pregnancy test within 72 hours prior to the initiation of therapy will be required for women of childbearing potential.
Highly effective contraception methods include: • Total abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception • Male or Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment • Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
• Combination of any two of the following (a+b or a+c, or b+c): a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Note: Female patients of childbearing age are defined as follows: • Patients with regular menses • Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding • Women who have had tubal ligation Female patients may be considered to NOT be of childbearing potential for the following reasons: • The patient has undergone total abdominal hysterectomy with bilateral salpingooophorectomy or bilateral oophorectomy • The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months Additional Cohort II inclusion Only: 3.1.13 International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. 3.1.14 Participant receiving corticosteroids may continue as long as their dose is stable for at least 4 weeks prior to initiating protocol therapy. 3.1.15 Participant must agree not to breastfeed during the study or for 150 days after the last dose of study treatment.

Exclusion Criteria
Patients will not be eligible for study entry if any of the following criteria are met: 3.2.9 Known brain or leptomeningeal metastases, except if stable for greater than 28 days following definitive treatment. Definitive treatment is defined as whole brain radiation, gamma-knife surgery, surgery, or any combination of the above. The patient must have no new or progressive signs or symptoms related to the CNS disease and must be either off or taking a stable dose of corticosteroids. A scan to confirm the absence of brain metastases is not required. Patients with spinal cord compression may be considered if they have received treatment, either surgery or radiation for this and evidence of clinically stable disease for 28 days.

3.2.12
History of bowel obstruction within 3 months, or other reason preventing effective oral administration of medication.

3.2.13
Known allergic reactions attributed to niraparib or its components.

3.2.
14 Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

3.2.15
Patients with a history of other malignancy ≤ 3 years prior to registration, with the exceptions of a) cone-biopsied in situ carcinoma of the cervix uteri; b) basal or squamous cell carcinoma of the skin. All second malignancies in this context should be discussed with the PI.

3.2.16
Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, social/ psychological issues.

Inclusion of Women and Minorities
Women of all races and ethnic groups are eligible for this trial. This study is designed to include minorities as appropriate. However, the trial is not designed to measure differences in intervention effects. The population of Southern Ontario is ethnically diverse and the proportion of different ethnic groups in the community is provided in the table below. Universal access to health care will ensure that there is no discrimination on the basis of race or gender (Guide to Canadian Human Rights Act: www.chrc-ccdp.ca/public/guidechra.pdf ). Individual hospital registries and databases do not routinely collect racial data, under the direction of the Canadian Human Rights Code.
The population demographics and distribution of minorities in Canada is included in the following table: Data from our consortium has been compiled regarding the representation of minorities on previous clinical trials, and the distribution is as follows:

General Guidelines
The Central Office Coordinator at the Drug Development Program Central Office will enter eligible patients on study centrally. The required forms (Registration Checklist) will be provided upon site activation.
Following registration, patients should begin protocol treatment within 7 days. Issues that would cause treatment delays should be discussed with the Principal Investigator (cc the central office study coordinator). If a patient does not receive protocol therapy following registration, the patient's registration on the study may be cancelled. The Central Office Coordinator should be notified of cancellations as soon as possible.

Registration Process
Prior to registering a patient, each institution must have submitted all necessary regulatory documentation to the Central Office. The registration checklist will only be sent once this has been received.
No patient can receive protocol treatment until registration with the Central Office has taken place. All eligibility criteria must be met at the time of registration. There will be no exceptions. Any questions should be addressed with the Central Office prior to registration.
To register a patient, the following documents are to be completed by the research nurse or data manager and sent / faxed to the Central Office Coordinator: • Signed patient consent form • Registration Checklist CRF signed by the investigator To complete the registration process, the Central Office will review the checklist and once eligibility has been confirmed: • Assign a patient study number • Confirm the starting dose • Register the patient on the study • Fax or e-mail the confirmation worksheet with the patient study number and dose to the participating site To ensure immediate attention is given to the faxed checklist, each site is advised to also call the Central Office Coordinator listed on the front sheet. Patient registration will be accepted between the hours of 9am to 5pm ET Monday to Friday, excluding Canadian statutory holidays when the Central Office will be closed.

Agent Administration
Cohort I Niraparib 100 mg capsules will be administered orally continuously as a flat-fixed daily (QD) dose (100 mg, 200 mg or 300 mg daily). Capsules should be swallowed whole without chewing. Fasting is not required. Patients should take doses at approximately the same times each day. The patient will be requested to maintain a medication diary of each dose of study medication. However, the actual number of capsules taken by the patient must be calculated from the number of capsules dispensed and returned. The medication diary will be returned to clinic staff at the end of each cycle and reviewed by the study staff.
Patients must be instructed to return unused study drugs to the site at discontinuation or completion of treatment. The site personnel must ensure that the appropriate dose of the study drug is administered and that the drug accountability is performed.
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's malignancy. Initial dose of niraparib will be determined by Cycle 1 Day 1 weight and platelet count.

Cohort II
Niraparib 100 mg capsules will be administered orally continuously as a flat-fixed daily (QD) dose (100 mg, 200 mg or 300 mg daily). Capsules should be swallowed whole without chewing. Fasting is not required. Patients should take doses at approximately the same times each day. The patient will be requested to maintain a medication diary of each dose of study medication. However, the actual number of capsules taken by the patient must be calculated from the number of capsules dispensed and returned. The medication diary will be returned to clinic staff at the end of each cycle and reviewed by the study staff.
Patients must be instructed to return unused study drugs to the site at discontinuation or completion of treatment. The site personnel must ensure that the appropriate dose of the study drug is administered and that the drug accountability is performed.
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's malignancy.\ TSR-042 will be administered via a 30-minute (-5-minute/+15-minute infusion window allowed) IV infusion on Day 1 of every 21-day cycle (every 3 weeks) at 500 mg on cycles 1 to 4, followed by 1,000 mg on Day 1 of every 42-days (every 6 weeks) thereafter until the patient discontinues study treatment. TSR-042 can be continued for a maximum of 2 years.
Vital signs monitoring during the (pre and post) infusion of TSR-042: Vital signs (blood pressure, heart rate, temperature, respiratory rate) will be done with the following frequency (schedule): There is no expected drug interaction.  Table 5.1-1 and section 6.1

General Concomitant Medication and Supportive Care Guidelines
All concomitant medications administered during study treatment will be recorded in source and eCRFs.

Hematopoietic Growth Factors
Prophylactic cytokine (Granulocyte Colony-Stimulating Factor [GCSF]) administration should not be given in the first cycle of the study, but may be administered in subsequent cycles according to local guidelines and Section 6.

Anticoagulants and Antiplatelets
The niraparib safety profile includes risk for thrombocytopenia; therefore, patients should be advised practice caution with anticoagulation and antiplatelet drugs. Patients who require such an agent during participation in the study are allowed to continue with close clinical monitoring.

Anticancer Therapy
No other anticancer therapy is permitted during the course of the study treatment for any patient. If the patient discontinues study treatment, this restriction no longer applies, however the patient will remain enrolled in the study for the purpose of collecting subsequent outcomes. Palliative radiotherapy (excluding the pelvic region and/or palliative radiotherapy encompassing >20% of the bone marrow within 1 week of the first dose of study treatment) is allowed for pre-existing small areas of painful metastases that cannot be managed with local or systemic analgesics as long as no evidence of disease progression is present.

Other Concomitant Medications
Niraparib has potential to weakly induce cytochrome P450 (CYP)1A2 in vitro; therefore, patients should be advised to use caution with drugs that are the sensitive substrates for CYP1A2.
Live vaccines within 14 days prior to the first dose of study treatment are not allowed. Seasonal flu vaccines that do not contain live viruses are allowed. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, bacille Calmette-Guerin, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. Intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.
TSR-042 only: Systemic glucocorticoids for any purpose other than to manage symptoms of suspected irAEIs. (Note: Use of inhaled steroids, local injection of steroids, topical steroids, and steroid eye drops are allowed). If medically deemed necessary (e.g., acute asthma or chronic obstructive pulmonary disease exacerbation), Investigators are allowed to use their judgment to treat patients with systemic steroids. In such cases, systemic steroids should be stopped at least 24 hours prior to the next dose of TSR-042 Any other medication which is considered necessary for the patient's welfare, and which is not expected to interfere with the evaluation of the study drug, may be given at the discretion of the Investigator. No other investigational agents are permitted during the entire duration of treatment with study drug.

Miscellaneous
Patients must not donate blood during the study or for 90 days after the last dose of study treatment, in cohort I and II.
A whole blood sample will also be collected for cytogenetic analysis (mutations of select myeloidassociated genes). Testing completed as part of standard of care is sufficient as long as the methods are acceptable to the Sponsor's Scientific Director. The study site must receive a copy of the hematologist's report of aspirate/biopsy findings (which must include a classification according to World Health Organization criteria) and other sample testing reports related to MDS/AML. Report data will be entered into EDC on the appropriate eCRF pages, and the site must keep a copy of the report with the patient's study file.

Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies: General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.
• Necessity for treatment with another anti-cancer treatment prohibited by this protocol.

5.4
Duration of Follow Up .

Criteria for Removal from Study
Patients will be removed from study when any one of the criteria below applies: The reason for study removal and the date the patient was removed must be documented in the Case Report Form.

General Guidelines: Niraparib
Dose modifications are listed in Table 6.1-1. Once the dose of study treatment has been reduced, dose re-escalation is not permitted.

NOTES
A. Objective disease progression is measured per RECIST 1.1 (see Section 11.1). B. Radiological assessments with CT scans need to be performed, with window of +/-7 days from the date CT is due C. Until adverse events resolves to < grade 2 (or baseline values), becomes stabilized or is no longer related to study treatment. In the case patient discontinuation is due to adverse event or clinically significant lab value, the patient needs to be followed weekly for 4 weeks after last dose (see Section 7.6), and then monthly until resolution of adverse event. All visits are to occur with a window of +/-3 days from the date of scheduled review. D. AML/MDS development will be followed every 3 months +/-2 weeks for a maximum of 2 years E. Patients who withdraw consent will no longer be followed F. Patient will be followed up for 2 years If the toxicity requiring dose interruption has not resolved to ≤ CTCAE Grade 1 or baseline during the maximum 4 weeks (28 days) dose interruption period, and/or the patient has already undergone the maximum number of dose reductions or reached the minimum dose of 100 mg QD, the patient must permanently discontinue treatment with niraparib.
For major surgery while on treatment, up to 28 days of drug interruption is allowed.
All dose interruptions and reductions (including any missed doses), and the reasons for the reductions/interruptions, are to be recorded in the electronic case report from (eCRF). If dose interruption or modification is required at any point on study because of hematologic toxicity, to ensure safety of the new dose, weekly blood draws for CBC will be required for an additional 4 weeks after the AE has been resolved to the specified levels, after which monitoring every 4 weeks may resume. Weekly blood draws for CBC can be collected either at study site or local laboratories. If the hematologic toxicity has not recovered to the specified levels within 4 weeks (28 days) of the dose interruption period, and/or the patient has already undergone the maximum dose reductions (to a minimum dose of 100 mg QD) then the patient must permanently discontinue treatment with niraparib.
Any patient requiring transfusion of platelets, red blood cells transfusion (except on the first occurrence), or hematopoietic growth factor support must undergo a niraparib dose reduction upon recovery if study treatment is resumed. If no further reductions can be made, niraparib must be permanently discontinued.
The treating physician may consider referral to a hematologist for further evaluation if the treatment-related hematologic toxicities have not recovered to ≤ Grade 1 or baseline within 4 weeks. If a diagnosis of MDS/AML is confirmed by a hematologist, the patient must permanently discontinue study treatment. No change in dose <100x10 9 /L -75x10 9 /L First occurrence: Hold until platelet counts are ≥100x10 9 /L, with weekly CBC until recovery. Weekly CBCs will continue to be

Platelet count
Management/Next Dose for Niraparib monitored for an additional 4 weeks after recovery to ≥100x10 9 /L. Resume at same dose level, or reduced dose based on clinical judgement.
Second occurrence: Hold until platelet counts are ≥100x10 9 /L, with weekly CBC until recovery. Weekly CBCs will continue to be monitored for an additional 4 weeks after recovery to ≥100x10 9 /L. Resume at a reduced dose. <75x10 9 /L Hold until platelet counts are ≥100x10 9 /L, with weekly CBC until recovery. Weekly CBCs will continue to be monitored for an additional 4 weeks after recovery to ≥100x10 9 /L. Resume drug with one dose-level reduction. Hematologic adverse reaction requiring transfusion For patients with platelet count ≤10,000/μL, platelet transfusion should be considered. If there are other risk factors such as co-administration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet count. Resume niraparib at a reduced dose. ▪ If platelet count has not reverted within 28 days of interruption to ≥100x10 9 /L, then the patient should be discontinued. ▪ For patients with platelet count ≤ 10x10 9 /L , prophylactic platelet transfusion per guidelines is to be considered [102]. ▪ For patients taking anticoagulation or antiplatelet drugs, consider the risk/benefit of interrupting these drugs and/or prophylactic transfusion at an alternate threshold. ▪ Patients requiring more than two dose reductions or reduction below 100mg will be discontinued.  Hold until neutrophil count is ≥1.5x10 9 /L, with weekly CBC until recovery and continue to monitor weekly CBC for an additional 4 weeks. Resume at a reduced dose.
Grade 4: <0.5 x10 9 /L Hold until neutrophil count is ≥1.5x10 9 /L, with weekly CBC until recovery and continue to monitor weekly CBC for an additional 4 weeks. Resume at a reduced dose. ▪ If neutrophil count has not reverted within 28 days of interruption to ≥1.5x10 9 /L, then the patient should be discontinued. ▪ Patients requiring more than two dose reductions or reduction below 100mg will be discontinued. Hold until hemoglobin is ≥90 g/L, with weekly CBC until recovery and continue to monitor weekly CBC for an additional 4 weeks. Resume at reduced dose. Grade 4: Life-threatening consequences; urgent intervention indicated Hold until hemoglobin is ≥90 g/L, with weekly CBC until recovery and continue to monitor weekly CBC for an additional 4 weeks. Resume at a reduced dose.
▪ If hemoglobin level has not reverted within 28 days of interruption to ≥90x10 9 /L, then the patient should be discontinued. ▪ Patients requiring more than two dose reductions or reduction below 100 mg will be discontinued.
There is no recommendation for lymphopenia or total white blood count. Hold until AE resolves to baseline or ≤Grade 1 (controlled). Resume with one dose level reduction.

Grade 4
Hold until AE resolves to baseline or ≤Grade 1 (controlled). Resume with one dose level reduction. ▪ Patients with toxicities that do not resolve within 28 days will be discontinued. ▪ Patients requiring more than two dose reductions or reduction below 100 mg will be discontinued. ▪ Dose reductions for any Grade 2 events that are bothersome to the patient will be permitted per Investigator judgement. This table only applies to non-hematological adverse events considered related to study medication and considered clinically significant as per investigator judgement. Clinically non-significant, treatable or reversible lab abnormalities including, but not limited to alkaline phosphatase or gamma-glutamyl transferase, uric acid, or electrolyte abnormalities do not require dose modifications.

GENERAL GUIDELINES: TSR-042
AEs (both non-serious and serious) associated with TSR-042 exposure may represent an immunologic etiology. These AEs may occur shortly after the first dose or several months after the last dose of treatment.
In general, TSR-042 must be withheld for drug-related Grade 3 toxicities, as well as for certain immune-related adverse events of interest (irAEIs), but may be resumed upon recovery to Grade ≤1; TSR-042 will be permanently discontinued for any drug-related Grade 4 AE. TSR-042 must be permanently discontinued for certain irAEIs as described in Table 6.2-1.
The specific immune-related AEs typically observed with anti-PD-1 antibodies will be managed according to the American Society of Clinical Oncology Clinical Practice guidelines summarized below [103].

Immune-related Adverse Events of Interest and Guidelines for Management
Given the mechanism of action of TSR-042, it is anticipated that activation of cellular immune system can be manifested as immune-related AEs. Based on available safety data from checkpoint inhibitors, treatment emergent adverse events (TEAEs) with the specific grades listed below were selected as immune-related adverse events of interest (irAEIs). The list of irAEIs may be updated upon emerging data.
Refer to Table 6.2-1 for details on the management of TSR-042 dose delays and discontinuation for specific irAEIs. Detailed guidance for the administration of rescue medications and supportive care are available below. For all irAEIs listed in Table 6.2-1, TSR-042 should be withheld until the patient is clinically and metabolically stable and AEs have resolved to Grade ≤1. If systemic steroids are used as a part of irAEI management, the total dose of daily steroids should be equal to or less than 10mg prednisone at the time of resuming TSR-042.
All treatment delays (including any missed doses) and discontinuations, and the reason for delays or discontinuation of TSR-042, should be documented. Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; T1DM = type 1 diabetes mellitus; ULN = upper limit of normal. a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by ≥50% relative to baseline and lasts for at least 1 week, then study treatment should be discontinued.
b Upon resolution within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 to 50 mL/h). Otherwise, study treatment will be withheld until symptoms resolve, and the patient should be pre-medicated for the next scheduled dose.

Rescue Medications and Supportive Care Guidelines
During treatment with TSR-042, patients should receive appropriate supportive care measures for AEs as deemed necessary by the treating Investigator, including but not limited to the items outlined below. Prophylactic cytokines (eg, GCSF) should be administered according to current ASCO guidelines [104]. Note: It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or skin photography as part of the evaluation of the AE. The following sections detail specific guidance by type of AE.

Pneumonitis
• Treat with systemic corticosteroids, oral for Grade 2 (e.g., 0.5 to 1 mg/kg/day of prednisone or equivalent) and IV for Grade 3 or 4 (e.g., 1 to 2 mg/kg/day of prednisone or equivalent).
• Administer additional anti-inflammatory measures, as needed.
• Taper corticosteroids when symptoms improve to Grade 1 or less over no less than 4 weeks.
• If Grade 2 and no improvement or worsening over 2 weeks, treat as Grade 3 or 4.
• Consider prophylactic antibiotics for opportunistic infections in the case of prolonged steroid administration.

Diarrhea/Colitis
• Monitor carefully for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).
• All patients who experience diarrhea/colitis should be advised to drink liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion.
• For Grade 2 diarrhea/colitis that persists >3 days, administer oral corticosteroids (eg, 0.5 to 1.0 mg/kg/day of prednisone or equivalent). If symptoms persist or worsen with steroids, treat as Grade 3 or 4.
• For Grade 3 or 4 diarrhea/colitis that persists >3 days, treat with IV steroids (eg, 1 to 2 mg/kg/day of prednisone or equivalent) followed by high-dose oral steroids.
• Taper corticosteroids when symptoms improve to Grade 1 or less over no less than 4 weeks.

Type 1 Diabetes Mellitus or Grade 3 or 4 Hyperglycemia
For type 1 diabetes mellitus and for Grade 3 or 4 hyperglycemia associated with metabolic acidosis or ketonuria, insulin replacement therapy is required.

Hypophysitis
• Treat with systemic corticosteroids, oral for Grade 2 (eg, 0.5 to 1 mg/kg/day of prednisone or equivalent) and IV for Grade 3 or 4 (eg, 1 to 2 mg/kg/day of prednisone or equivalent).
• Taper corticosteroids when symptoms improve to Grade 1 or less over no less than 4 weeks.
• Replacement of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism
Thyroid disorders have been reported with other PD-1 inhibitors occurring at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
• Grade 3 or 4 HYPERthyroidism: Treat with an initial dose of IV corticosteroids followed by oral corticosteroids (eg, 0.5 to 1 mg/kg/day of prednisone or equivalent). Taper corticosteroids when symptoms improve to Grade 1 or less over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.
• Grade 2 to 4 HYPOthyroidism: Thyroid hormone replacement therapy, with levothyroxine or liothyronine, is indicated per standard of care.

Hepatitis
• Treat with systemic corticosteroids, oral for Grade 2 (initial dose of 1 to 2 mg/kg/day of prednisone or equivalent) and IV for Grade 3 or 4 (1 to 2 mg/kg/day of prednisone or equivalent).
• Taper corticosteroids when symptoms improve to Grade 1 or less over no less than 4 weeks.

Renal Failure or Nephritis
• Treat with systemic corticosteroids, oral for Grade 2 (initial dose of 0.5 to 1 mg/kg/day of prednisone or equivalent) and IV for Grade 3 or 4 (1 to 2 mg/kg/day of prednisone or equivalent).
• Taper corticosteroids when symptoms improve to Grade 1 or less over no less than 4 weeks.

Management of Infusion-Related Reactions
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Table 6.2-2. shows treatment guidelines for patients who experience an infusion-related reaction associated with administration of TSR-042. Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section 7.1.1.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting as an SAE in addition to routine reporting.
In addition, hospitalizations for routine procedures, protocol treatment, blood sampling, investigations and tissue biopsies are NOT considered SAE in this protocol.

Expected Adverse Events for Niraparib
The common expected drug related adverse events seen in Phase I studies of niraparib involving 144 patients include fatigue, nausea, anemia, thrombocytopenia, decreased appetite, neutropenia, vomiting, constipation, leukopenia, diarrhea, insomnia, dyspnea, electrocardiogram (ECG) QT prolongation, headache, stomatitis, hyponatraemia and alopecia. The majority of these events were managed with dose interruption and/or reduction. There were no new safety concerns from the recently completed phase III niraparib maintenance study in ovarian cancer (PR-30-5011-C or NOVA trial). The treatment discontinuation rate in that study was 14.7% for the niraparib arm and 2.2% for control.
Myelodysplastic syndrome (MDS) and AML have been observed in patients receiving treatment with olaparib, a PARP inhibitor, and represent a potential risk for patients receiving niraparib [78]. In the phase III NOVA trial there was no increase incidence of MDS/AML seen in the niraparib treated patients (1.3%) compared with patients who received placebo (1.2%). However, there exists the potential for an increased risk for the development of MDS/AML due to numerous insults to the DNA damage repair pathway.
For complete list of adverse event for Niraparib, please refer to the current Investigator's Brochure of Niraparib.

Adverse Events of Special Interest (AESI)
An Adverse Event of Special Interest is defined as any AE (serious or non-serious) that is of scientific and medical concern specific to the study treatment, for which ongoing monitoring and rapid communication to the Sponsor Institution and to TESARO/GSK is required.
Adverse Events of Special Interest (AESI) for niraparib include the following: • Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

• Secondary cancers (new malignancies [other than MDS or AML])
• Pneumonitis • Embyro-fetal toxicity AESIs should be reported on SAE Report Forms whether serious or not, as follows: • MDS and AML along with other secondary cancers should be reported to the Sponsor Institution and to TESARO/GSK upon awareness for any patient who has received niraparib (regardless of the timeframe since the last dose).
• Pneumonitis should be reported to the Sponsor Institution and to TESARO/GSK through 90 days after the last dose of niraparib.
• Embryo-fetal toxicity should be reported as outlined in the Pregnancy reporting section.
For complete list of adverse event for TSR-042, please refer to the current Investigator's Brochure of TSR-042.

Adverse Event Characteristics
• CTCAE term (AE description) and grade: Serious adverse drug/biologic experience: Any event is an AE occurring at any dose that results in any of the following outcomes: • Death • A life-threatening AE (The patient was, in the view of the Investigator, at immediate risk of death from the event as it occurred. It does not mean that the event, had it occurred in a more severe form, might have caused death). • Hospitalization or prolongation of existing hospitalization (Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline is not considered to be an AE). • A persistent or significant disability/incapacity (A substantial disruption of a person's ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, accidental trauma (i.e., sprained ankle) that may interfere or prevent everyday life functions but do not constitute a substantial disruption). • A congenital anomaly/birth defect.
• Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition (Examples include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in hospitalization or the development of drug dependency or drug abuse).
Any secondary malignancy possibly related to cancer treatment (including AML/MDS) should be reported as an SAE. A secondary malignancy is one related to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy).
Events not considered to be serious adverse events are: • hospitalizations for the routine treatment or monitoring of the studied indication, not associated with any deterioration in condition, • treatment, which was elective or pre-planned, for a pre-existing condition that is unrelated to the indication under study and did not worsen, • admission to a hospital or other institution for general care, not associated with any deterioration in condition, or • treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of serious given above and not resulting in hospital admission.
Any SAE occurring after the patient has provided informed consent and until 30 days after the patient has stopped study participation must be reported. This includes the phase in which the study protocol interferes with the standard medical treatment given to a patient (e.g. treatment withdrawal during screening phase, change in treatment to a fixed dose of concomitant medication). Serious adverse events occurring more than 30 days after study drug discontinuation need only be reported if a relationship to niraparib or TSR-042 is suspected.
Unexpected adverse drug/biologic experience: Any adverse drug/biologic experience, the nature, frequency, or severity of which is not consistent with the product monograph, or not consistent with the risk information described above as a protocol-specific expected adverse event (see "Expected Adverse Events and Protocol-Specific Expedited Adverse Event Reporting Exclusions", above).

Sponsor Notification
Any serious adverse event must be reported to the Central Office within 24 hours of the Investigator at the site learning of the event by completion of an SAE form. The adverse event must be completely described in the SAE report form.
Signs and symptoms surrounding the SAE which occur during or following the course of drug administration must be reported in detail on the subject's SAE report. This description is to include the CTCAE term, time of onset, duration, CTCAE grade, and possible relationship to study treatment, required therapy, and outcome. The SAE Report Form must be signed by the investigator. The subject should be followed until the SAE is resolved, or until in the opinion of the Principal Investigator, reversal of the reaction is not likely to occur.

SAE Follow-up
Follow-up SAE reports are subject to the same timelines as the initial report, and are sent to the same parties to whom the original Serious Adverse Event Form was sent. A new serious adverse event form is completed for the follow-up, stating that this is a follow-up to the previously reported serious adverse event. Each re-occurrence, complication or progression of the original event should be reported as a follow-up to that event. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, and whether the patient continued or discontinued study participation.

Routine Adverse Event Reporting
Data on all adverse experiences/toxicities regardless of seriousness must be collected for documentation purposes only. Adverse events (AEs) will be collected from the time of informed consent to 30 days after last study drug administration. AEs that occur before the first study drug administration, concomitant illnesses, which existed before study entry, but did not worsen during the treatment period and any pre-existing conditions are known as "baseline symptoms" and by definition are "unrelated" to study drug. Any AEs related to biopsy will be recorded in source and CRFs. All AEs, regardless of the source of identification (e.g., physical examination, laboratory assessment, electrocardiograms [ECG], reported by patient), must be documented.

Clinical Laboratory Abnormalities:
All clinically significant CTCAE v4.0 gradable abnormal laboratory or hematologic events that are ≥ grade 2 will be recorded in source and in study CRFs. These abnormal laboratory results will be followed until the related AE resolves to ≤grade 1 or baseline as per Section 5.4. Clinically significant laboratory AEs will include, but not be limited to, those that result in any of the following: • Change in study drug dosing; or • Administration of a concomitant medication; or • AE considered clinically significant as per the Study Investigator as documented in their dictation

Documentation of Adverse Events
All AEs must be captured in the source documents, as well as reported in electronic document capture (EDC) system. AEs reported using SAE forms must also be reported in EDC system.
All serious and non-serious AEs occurring from informed consent to 30 days after last study drug administration must be recorded in source and CRFs. The Investigator should review all documentation (e.g., hospital progress notes, laboratory, or diagnostic reports) relative to the event being reported.

Follow-Up of AEs and SAEs
SAEs and AEs should be followed for 30 days after the last dosing of study drug/biologic or until they are resolved (< grade 2 or baseline values), stabilized, or the patient is lost to follow-up and cannot be contacted. Additional investigations (e.g., laboratory tests, diagnostic procedures, or consultation with other healthcare professionals) may be required to completely investigate the nature and/or causality of an AE or SAE. If the patient dies during the study or within 30 days following the last dose of study medication, any postmortem findings (including histopathology) should be provided to the Central Office. CRF data should be updated with any new information as appropriate.

Pregnancy
Any pregnancy of a study subject or of a study subject's partner that occurs during study participation should be reported for pregnancies that occur up to 30 days after the last dose of study medication. To ensure patient safety each pregnancy must also be reported to TESARO/GSK within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of birth, and the presence or absence of any birth defects, congenital abnormalities or maternal and newborn complications.

Reporting Product Quality Complaints for Niraparib and TSR-042
Any written, electronic or oral communication that alleges dissatisfaction related to manufactured clinical drug product with regards to its manufacturing, testing, labeling, packaging, or shipping, must be reported by the Principal Investigator or qualified designee to TESARO/GSK within 1 working day of first becoming aware of the possible defect to TESARO/GSK QA at tesaro.qa@gsk.com.The product and packaging components in question, if available, must be stored in a secure area under specified storage conditions until it is determined whether the product is required to be returned for investigation of the defect. If the product complaint is associated with an SAE, the SAE must be reported separately in accordance with the protocol, and the SAE report should mention the product quality complaint.

Special Situations: Abuse, Misuse, Medication Errors, Overdose, and Accidental or Occupational Exposure
• Abuse: is the persistent or sporadic, intentional excessive use of the study treatment which is accompanied by harmful physical or psychological effects.
• Misuse: medicinal product is intentionally and inappropriately used not in accordance with the authorized/approved product information.
• Medication error: is any preventable incident that may cause or lead to inappropriate study treatment use or patient harm while the study treatment is in the control of the health care professionals or patients. Such incident may be due to health care professional practice, product labeling, packaging and preparation, procedures for administration, and systems, including the following: prescribing, order communication, nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use.
• Overdose: is a deliberate or accidental administration of study treatment to a study patient, at a dose greater than that which was assigned to that patient per the study protocol and under the direction of the Investigator. If an overdose with a TESARO/GSK product, the Sponsor Institution and TESARO/GSK should be notified immediately, and the patient should be observed closely for AEs. Associated AEs should be treated and monitored by the Investigator. The dosage of study drug administered, any associated AEs, and/or treatment provided to the patient because of the overdose, should be reported.
• Accidental /Occupational exposure: is the unintentional exposure to a study treatment as a result of one's professional or non-professional occupation, or accidental exposure to a non-professional to whom exposure was not intended (i.e., study product given to wrong patient).
Reporting Special Situations: All occurrences of abuse, misuse, medication error, overdose, and accidental or occupational exposure associated with a TESARO/GSK product must be reported on a Special Situations Report Form to the Sponsor Institution and to TESARO/GSK within 5 business days of awareness regardless of whether or not an AE or SAE has occurred. If the abuse, misuse, medication error, overdose, or accidental / occupational exposure is associated with an AE, an SAE Report Form must also be submitted to the Sponsor Institution and to TESARO/GSK within 24 hours of awareness.

Data Safety and Monitoring Board
The Drug Development Program Data Safety and Monitoring Board, an independent group of experts, will be reviewing the data from this research throughout the study to see if there are unexpected or more serious side effects than described in the consent.

PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agent administered in this study can be found in Section 7.1. , is an orally available, potent, highly selective PARP-1 and -2 inhibitor. The excipients for niraparib are lactose monohydrate and magnesium stearate.

Investigational agent Manufacturing
Niraparib is manufactured by TESARO/GSK.

Investigational agent Packaging and Labeling
Niraparib is supplied by TESARO/GSK as 100 mg capsules packaged in high-density polyethylene (HDPE) bottles with child-resistant plastic closures. TESARO/GSK provided Study drug will be meet all regulatory requirements and will be compliant with regulations.

Investigational agent Handling and Storage
Investigational agent will be stored under secure (with limited access), and temperature-controlled conditions for the duration of the study. Investigational agent bottles will be stored at ambient temperature (i.e.15-30C) in an area accessible only to authorized staff. Patients will be asked to store their one-month supply of drug at ambient temperature. Study drug inventory forms will be kept by the Investigator, or designee.

Availability
Niraparib is provided under a Collaborative Agreement between the Sponsor and the agent manufacturer TESARO/GSK.

Investigational Agent Ordering and Shipping
Niraparib will be supplied by TESARO/GSK to each study site. The site Principal Investigator, or authorized study personnel, upon receipt of the study medication supplies, will conduct an inventory and acknowledge receipt to TESARO/GSK, or designee.
Study medication should only be dispensed once a patient has (1) signed an informed consent form (ICF), (2) met all eligibility criteria for entry into the study, (3) completed all screening and continuing eligibility requirements, and (4) been assigned a patient identification number.

Agent Accountability
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of all agents received using their site-specific drug accountability log. The drug accountability log includes information including the enrollment number, amount dispensed, and amount returned to the pharmacy, if applicable. Product returned to the pharmacy will be stored under the same conditions as products not yet dispensed but will be marked as 'returned' and kept separate from the products not yet dispensed. All dispensing and accountability records will be available for Sponsor review. When the study monitor visits, he/she will reconcile the drug accountability log with the products stored in the pharmacy. The pharmacist will dispense study drug for each patient according to the protocol and pharmacy manual, if applicable.

TSR-042
TSR-042 is an IgG4 antibody and will be supplied as a solution in vials containing 500 mg (50 mg/ml).

Investigational Agent Packaging, Labeling and Storage
TSR-042 for injection is supplied in vials containing 500 mg at a concentration of 50 mg/mL.

Investigational Agent Availability
TSR-042 is provided under a Collaborative Agreement between the Sponsor and the agent manufacturer TESARO/GSK.

Investigational Agent Ordering and Shipping
TSR-042 will be supplied by TESARO/GSK to each study site. The site Principal Investigator, or authorized study personnel, upon receipt of the study medication supplies, will conduct an inventory and acknowledge receipt to TESARO/GSK, or designee.
Study medication should only be dispensed once a patient has (1) signed an informed consent form (ICF), (2) met all eligibility criteria for entry into the study, (3) completed all screening and continuing eligibility requirements, and (4) been assigned a patient identification number.

Investigational Agent Accountability
The Investigator or designee is responsible for maintaining accurate dispensing records of the study treatment throughout the clinical study. The study treatment accountability log includes information including a patient identifier, amount and date dispensed, and amount and date returned to the pharmacy, if applicable. Product returned to the pharmacy will be stored under the same conditions as products not yet dispensed but will be marked as 'returned' and kept separate from the products not yet dispensed.
All dispensing and accountability records should be stored in accordance to the Sponsor institution regulations. The pharmacist will dispense study treatment for each participant according to the protocol and storage and handling manual, if applicable.

Biomarker Studies
Correlative studies evaluating tumor biology relevant to endometrial cancer will focus on (1) evaluating baseline status of PTEN (using standard IHC to identify PTEN loss), (2) tumor MSI status using a custom IHC panel, (3) analysis of BRCA1/2 and other HRD genes, and (4) genomic sequencing, and immune infiltration. All Correlative Studies will be conducted following developed standard operating procedures, for both sample acquisition and performing individual assays.
Patient who have undergone molecular profiling through different programs, including VENUS (Molecular and Immunological characterization of gynecological malignancies, NCT03420118), and OCTANE (Ontario-wide Cancer TArgeted Nucleic Acid Evaluation, NCT02906943), the molecular data will be recorded as part of this current trial.

Collection of Specimen(s)
Paraffin embedded archival blocks are preferred, however if blocks cannot be released 25 unstained slides cut at 4 microns thick each mounted on positively charged (for IHC) or uncharged (sequencing) slides are also acceptable. All correlative analyses will be performed in the archival specimens of all patients.

PTEN Immunohistochemistry Analysis
An optimized PTEN antibody will be used and immunohistochemistry (IHC) analysis will be carried out on the Ventana Benchmark XT autostainer using the Ultra-view detection system for PTEN at the Applied Molecular Profiling Laboratory or on another system if employed at our institute at the time of analysis. Importantly, PTEN immunostaining has a built-in control on each section as the tumor stromal fibroblasts and endothelial cells show strongly positive (2+) staining. Positive staining is defined as >90%. Loss of PTEN expression is defined as <1% cytoplasmic staining in tumor cells. Intermediate levels of staining are scored as heterogeneous pattern [96]. For the purpose of analysis, cases with negative and heterogenous staining are considered to have PTEN loss, whereas positive cases PTEN retained [105].

MxIF Analysis
4 µm slides will be made from formalin-fixed and paraffin-embedded archival tumor tissues (or fresh tumor biopsies, when archival tissue is unavailable) for multiplex immunofluorescence (MxIF). Tissues will be stained using a MxIF platform developed by the General Electric Global Research Center (GE-GRC; New York) and adapted at the Sunnybrook Research Institute's Biomarker Imaging Research Lab (BIRL; Toronto). Tissues will be examined by MxIF for markers of various immune cell populations including: T cells (CD3, CD4, CD8), B cells (CD20), NK cells (CD56), epithelial cells (cytokeratin), myeloid cells (CD68), as well as for the expression of immune checkpoint markers (PD-1, PD-L1). MxIF images will be analyzed using software developed by the GE-GRC, which supports single-cell phenotyping using additional cell compartment segmentation markers: DAPI, ribosomal S6, and NaKATPase. Altogether, MxIF analysis of the tumor microenvironment in these patient samples will allow us to characterize the spatial distribution of infiltrating immune cells and correlate these data with clinical outcomes. Immunohistochemistry can be also performed for the immune markers.

MSI analysis
Archival paraffin slides will be stained immunohistochemically using primary antibodies to evaluate MSI status. These archived samples will then be evaluated by the specific companion diagnostic test at the Applied Molecular Profiling Laboratory. MSI testing will be performed in samples with >70% tumor cells, as determined by examination of a representative hematoxylin and eosin-stained section of the tumor. IHC staining using anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2 will be performed on archival tumor samples. Loss of mismatch-repair protein expression will be defined by lack of nuclear staining in the lesional tissue. MSH-2 testing will be carried out on the Ventana Benchmark XT autostainer (already optimized, clone G219-1129, cat. no 760-4265, or equivalent if other antibodies are used in the future). All antibodies will be optimized for immunohistochemistry using the Ventana autostainer using positive/negative tissue specimens at the Applied Molecular Profiling Laboratory. The analysis will be performed by an expert pathologist. MSI /MMR (microsatellite instability MSI / mismatch repair protein -MMR) will be collected for all Cohort II patients from previous pathology report.

HRD status
A screening panel of several genes involved in cell cycle regulation, DNA replication, DNA recombination and repair pathways will be developed. The analyses will be performed with next generation sequencing (NGS) for mutations in HRD genes and/or IHC for expression levels.
Alternatively, the Myriad myChoice HRD test maybe employed to determine tumor HRD status.

Genomic analysis
Next Generation Sequencing technology will be used to profile tumor DNA to correlate genomic alterations with response. We propose targeted panel whole-exonic sequencing (UHN Advanced Molecular Diagnostics Lab -AMDL, CAP/CLIA; S. Kamel-Reid) or whole exome (or genome) sequencing (Genomics Program -Dr. Trevor Pugh), after examination of all slides available, the most suitable, representative blocks will be chosen. Where archival FFPE samples are utilized, blocks are preferred though 7 micron thick sections on 15-20 unstained slides and one H&E slide are acceptable. Biopsy samples will be assessed for quality and quantity of malignant cells. DNA will be extracted and checked for quality prior to genomic analysis.